Although 30% of patients with stroke are diabetic, and over 50% develop post-stroke hyperglycemia (HG), the clinical benefit of glucose normalization in the acute stroke setting is problematic controversial due to the risk of hypoglycemia. Moreover, both diabetes and HG are associated with worse neurological outcomes, lower reperfusion therapies efficacy, and aggravated vascular complications. Hence, there is an urgent need to identify novel targets for the development of treatments that mitigate these risks. Our long-term goal is to identify suitable drug targets to aid in the discovery of novel and clinically applicable therapies for improving stroke outcome. The objective of this application is to determine the role of endothelial-TXNIP in hyperglycemic stroke-induced neurovascular damage. Thioredoxin-interacting protein (TXNIP), a major intracellular regulator of redox/ glucose induced stress and inflammation, now known to be upregulated in stroke, presents a promising therapeutic target. In preliminary studies, we have demonstrated that HG mice have higher TXNIP expression and increased hemorrhage after an embolic stroke compared to wild type (WT) controls. These exciting findings have suggested that TXNIP as a promising therapeutic target in cerebral stroke. However, there are definite knowledge gaps concerning the specific contribution of vascular TXNIP to the inflammatory response in ischemia and reperfusion (tPA) injury. Therefore, our central hypothesis is that HG/ reperfusion- induced TXNIP expression sustains neurovascular injury through activation of NLRP3-inflammasome, vascular endothelial growth factor (VEGF), and matrix metalloproteinase (MMP) after stroke. This hypothesis will be tested in three specific: Aim 1: Test the hypothesis that HG exacerbates reperfusion injury by activating the TXNIP-NLRP3 inflammasome after stroke. Aim 2: Test the hypothesis that hyperglycemic stroke-induced TXNIP triggers VEGF and MMP mediated neurovascular damage. Aim 3: Test the hypothesis that a novel TXNIP inhibitor attenuates hyperglycemic stroke-induced neurovascular damage and functional deficits. Expected outcomes of the proposed research include: (1) Identification of hyperglycemic stroke induced- TXNIP as a key mediator of NLRP3 inflammasome formation, and (2) demonstration that hyperglycemic stroke induced-TXNIP-NLRP3 triggers VEGF and MMP-mediated neurovascular damage, using endothelial specific (EC)-TXNIP-/- mice, a specific NLRP3, MMP-9/2 and VEGF inhibitors, and reperfusion with IV-tPA (1.5 h). (3) Our study will be the first to use of the newly created specific inhibitors for TXNIP and NLRP3 to address whether therapeutic inhibition of TXNIP will improve long-term recovery and extent of the ischemic penumbra by using MRI-diffusion tensor imaging (DTI) in an embolic stroke. These studies may have far-reaching translational implications as the identification of vascular TXNIP, as key mediators of secondary injury will provide novel targets for therapeutic intervention in HG/diabetes associated neurovascular injury in stroke.